@article{409a2f82c19a4a6d968c58b0996e95da,
title = "Activity-dependent regulation of astrocyte GAT levels during synaptogenesis",
abstract = "Astrocytic uptake of GABA through GABA transporters (GATs) is an important mechanism regulating excitatory/inhibitory balance in the nervous system; however, mechanisms by which astrocytes regulate GAT levels are undefined. We found that at mid-pupal stages the Drosophila melanogaster CNS neuropil was devoid of astrocyte membranes and synapses. Astrocyte membranes subsequently infiltrated the neuropil coordinately with synaptogenesis, and astrocyte ablation reduced synapse numbers by half, indicating that Drosophila astrocytes are pro-synaptogenic. Shortly after synapses formed in earnest, GAT was upregulated in astrocytes. Ablation or silencing of GABAergic neurons or disruption of metabotropic GABA receptor 1 and 2 (GABA B R1/2) signaling in astrocytes led to a decrease in astrocytic GAT. Notably, developmental depletion of astrocytic GABA B R1/2 signaling suppressed mechanosensory-induced seizure activity in mutants with hyperexcitable neurons. These data reveal that astrocytes actively modulate GAT expression via metabotropic GABA receptor signaling and highlight the importance of precise regulation of astrocytic GAT in modulation of seizure activity.",
author = "Muthukumar, {Allie K.} and Tobias Stork and Freeman, {Marc R.}",
note = "Funding Information: We are grateful to S. Waddell (University of Oxford), G. Miesenb{\"o}ck (University of Oxford), J. Carlson (Yale University), V. Budnik (University of Massachusetts Medical School), B. Ganetsky (University of Wisconsin-Madison) and M. Tanouye (University of California, Berkley) as well as the Vienna Drosophila RNAi Center and the Bloomington Stock Center for generously providing fly stocks. We thank the Transgenic RNAi Project (TRiP) at Harvard Medical School (US National Institutes of Health NIGMS R01-GM084947) for providing transgenic RNAi fly stocks and/or plasmid vectors. The antibodies nc82, anti-PDF, anti-Fasciclin II and anti-Elav, developed respectively by E. Buchner, J. Blau, C. Goodman and G.M. Rubin, were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa. We thank the University of Massachusetts Medical School electron microscopy facility, in particular L. Strittmatter, for expert technical assistance with TEM studies. We thank C. Merlin for expert advice on real-time PCR experiments. We thank N. Fox for comments on the manuscript. We thank D. Bergles and all members of the Freeman laboratory for discussion on the manuscript. The project described was supported by Award Number S10RR027897 from the National Center For Research Resources. T.S. was supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (DFG). This work was supported by NINDS grant R01NS053538 (to M.R.F.). M.R.F. is an Investigator with the Howard Hughes Medical Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health. Publisher Copyright: {\textcopyright} 2014 Nature America, Inc. All rights reserved.",
year = "2014",
month = oct,
day = "1",
doi = "10.1038/nn.3791",
language = "English (US)",
volume = "17",
pages = "1340--1350",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "10",
}